CN100340550C - Method for preparing prochloraz - Google Patents

Abstract

The invention relates to a preparation method of imidamide, which uses 2,4,6-trichlorophenol, 1,2-dibromoethane, n-propylamine, imidazole and trichloromethyl carbonate as raw materials, and utilizes non-phosgene Route, through a simple and easy one-pot method, synthesize N-n-propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl]carbamoyl imidazole (imidamide). The present invention abandons traditional phosgene routes and pressurization, high-temperature, high-vacuum and reduced-pressure distillation, etc., which are unfavorable for large-scale synthesis, uses a green reagent—trichloromethyl carbonate (triphosgene), and adopts a "one-pot method" "Condensation shortens the route, and optimizes mild technical conditions such as cooling, suction filtration, recrystallization, and washing. The operation is safer and simpler, and the total yield is further improved, which is more conducive to environmental protection.

Description

The preparation method of imidamide

technical field

The invention relates to a preparation method of imidamide.

technical background

Imidamide is a kind of carbamoyl imidazole, which is a new type of broad-spectrum agricultural fungicide and a new generation of fruit fresh-keeping agent superior to thiabendazole. It has significant control effects on penicillium, anthracnose, and pedicle rot of citrus, and shaft rot and anthracnose of bananas. At the same time, it can also prevent and control rice blast, as well as diseases of wheat, rape, and tobacco in the north.

With different substituents, the bactericidal effect of carbamoyl imidazole is different, and the best effect is imidamide-N-n-propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl ] carbamoyl imidazole, its international common name is Prochloraz, and the trade name is Sprotak or Trimidal [see Sharvit Joseph, Pereferkovich Abraham Adolf.An Environmentally State Method ofPreparing A Certain Dialkylamine. EP 0403952, 1990; Sharvit Joseph. A henvel Pre ox Method of y paring Ethers for Use As Agrochemical Intermediates. EP 0404092, 1990; Du Weisong, Ning Binke, Ge Zhongxue, Qiu Yongsheng. The properties and synthesis of the fungicide prochloraz. Shaanxi Chemical Industry, 1998, 27(4): 24～26; Wang Xiaowei, Du Weisong, Ge Zhongxue, Qiu Yongsheng. Synthesis of N-propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl]-1H-imidazole-1-carboxamide. Synthetic Chemistry, 2002, 10:( 6): 506-509].

In the traditional synthetic method of imidamide (references as above), usually starting from 2,4,6-trichlorophenol, it needs to go through 1,2-dichloro(bromo)ethane etherification, propylamine substitution amination, phosgene Acylation, imidazole condensation and other four steps for synthesis. Among them, operations such as pressurization and high-vacuum decompression distillation are required, and the use of highly toxic reagent phosgene is involved. Therefore, it has disadvantages such as long route, large equipment investment, many safety hazards, and long process route, which is not conducive to industrial production.

Contents of the invention

The purpose of the present invention is to provide a kind of preparation method of imidamide for the defect that prior art exists, save the equipment that produces phosgene and the pressurization equipment of gas-liquid phase reaction, avoid highly toxic phosgene to pollute the environment; Adopt " one Pot method" simplifies the operation steps, shortens the reaction time, and is conducive to environmental protection. Simultaneously, in order to further reduce cost and environmental protection safety, except adopting green reagent---trichloromethyl carbonate (triphosgene), the present invention does not need high-pressure etherification, does not need high-vacuum decompression distillation.

The preparation method of imidamide of the present invention comprises the steps:

(1) 1,2-dibromoethane reacts with 2,4,6-trichlorophenate sodium to synthesize 1-bromo-2-(2,4,6-trichlorophenoxy)ethane, which is called intermediate Body I: 1,2-dibromoethane and 2,4,6-trichlorophenol sodium solution were refluxed for 5-15 hours, and the reflux was stopped when the aqueous phase was clear and pH=7.

(2) Intermediate I reacts with n-propylamine in ethanol solution to prepare N-2-[(2,4,6-trichlorophenoxy) ethyl] propylamine hydrobromide, which is called intermediate II;

(3) In the presence of trichloromethyl carbonate and triethylamine, N-n-propyl-N-[2-(2,4,6-tri Chlorophenoxy) ethyl] carbamoyl imidazole, i.e. imidamide.

In step (1), after the reaction between 1,2-dibromoethane and 2,4,6-trichlorophenate sodium, add chloroform to dissolve the solid, separate the oil layer, reclaim the solvent and excess 1,2-dibromoethane Alkanes, the residual liquid is cooled and solidified, suction filtered, and organic solvent recrystallized to obtain 1-bromo-2-(2,4,6-trichlorophenoxy)ethane (intermediate I), with a yield of about 87% . This step prepares the intermediate I through mild processes such as cooling, suction filtration, and recrystallization, so as to avoid pipe blockage caused by residual phenols during vacuum distillation and increase the yield.

The organic solvent used for recrystallization is petroleum ether, n-hexane or ether.

In step (2), the volume fraction of the ethanol solution is 75-100%, and the reflux time of the reaction between the intermediate I and n-propylamine is 10-30 hours.

After the reaction is complete, the solvent and excess n-propylamine are recovered, the residue is treated with hydrobromic acid, solidified, filtered with suction, and washed with an organic solvent to obtain N-2-[(2,4,6-trichlorophenoxy)ethyl]propylamine Hydrobromide, the yield is about 92%. This step directly obtains intermediate II with the method of salt formation, suction filtration, washing, avoids the use in the process of obtaining intermediate N-2-[(2,4,6-trichlorophenoxy) ethyl] propylamine in the past. The highly corrosive alkali sodium hydroxide and the flammable and explosive organic solvent ether are economical, safe and beneficial to industrial production.

The concentration of hydrobromic acid used for residue treatment is 15%-48% by mass.

The organic solvent used for washing is sherwood oil, n-hexane, diethyl ether, or carbon tetrachloride.

The directly prepared N-2-[(2,4,6-trichlorophenoxy)ethyl]propylamine hydrobromide was prepared for the first time as a white powdery solid with a melting point of 124-127°C. Its structure was confirmed by IR, ¹ Methods such as H NMR and elemental analysis were tested to show that they were correct.

Step (2) directly prepares N-2-[(2,4,6-trichlorophenoxy) ethyl] propylamine hydrobromide, takes it as intermediate II, avoids previous to intermediate N-2-[ (2,4,6-trichlorophenoxy) ethyl] propylamine complex vacuum distillation process in the purification process.

In step (3), to the chloroform solution of trichloromethyl carbonate, drop the chloroform solution of intermediate II and triethylamine, then add the chloroform solution of imidazole and triethylamine, reflux reaction for 4 to 8 hours, triethylamine The molar ratio of amine to intermediate II is 1.0-2.5:1, and the molar ratio of trichloromethyl carbonate to intermediate II is 0.38-0.33:1.00.

After the reaction is complete, the solvent is recovered, water is added to wash the residual solid, and the mixed solvent of toluene and petroleum ether is recrystallized to obtain N-n-propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl]amino Formyl imidazole (imidamide), the yield is about 85%.

The volume ratio of toluene to petroleum ether is 1.2-0.8:1.

Compared with the prior art, the present invention has the following advantages:

1, in step (1), because intermediate I is solid under room temperature, therefore can adopt the method for organic solvent recrystallization such as sherwood oil to carry out purification, thereby has saved complicated underpressure distillation operation, has not only greatly reduced equipment and The cost of energy consumption also increases the yield and improves the product purity. In the present invention, the product is purified by recrystallization to obtain colorless needle crystals with a yield of 87%.

2, in step (2), because intermediate II is solid, therefore can adopt the method for washing with organic solvents such as suction filtration, carbon tetrachloride to carry out purification, thereby saved prior art to N-2-[(2, The complex vacuum distillation operation (160°C-162°C/4mmHg) for the purification of 4,6-trichlorophenoxy)ethyl]propylamine greatly reduces the cost of equipment and energy consumption, and is also conducive to improving product purity.

3. In step (2), since the intermediate II is obtained by the salt-forming method, it is different from the existing process for preparing N-2-[(2,4,6-trichlorophenoxy)ethyl]propylamine as the intermediate Compared, after the process of complete reaction, reclaiming solvent and excess n-propylamine, in addition to reducing the high-vacuum decompression distillation step, the residue is alkalized with strong alkali sodium hydroxide, liquid separation, ether extraction of the aqueous layer, The combined organic layers were washed with water, dried, diethyl ether was evaporated in a water bath and many other processing steps. In the present invention, the treatment steps are salt formation, suction filtration, and washing. The steps are simple and easy to implement; more importantly, the use of highly corrosive strong alkali sodium hydroxide and organic solvents with flammable and explosive properties can be avoided. Ether, so it is economical and safe, greatly conducive to industrial production.

4. The present invention adopts the green reagent trichloromethyl carbonate (triphosgene), uses recrystallization to purify the product, and the process conditions are environmentally friendly and mild, eliminating unfavorable factors such as dangerous reagent phosgene and high vacuum decompression distillation, more energy-saving, It is safe, has high yield, and is easy to purify the product, so it is more suitable for industrial production.

Detailed ways

Example 1

Step 1: Take 150g (66.7mL, 0.8mol) of 1,2-dibromoethane in a 250mL three-neck flask, add 50mL of water, heat to boiling, add 2,4,6-trichloro Sodium phenoxide solution (dropped in about 1 h), continued to reflux for 10 h, stopped the reflux when the water phase was clear and pH = 7, cooled, added 20 mL of chloroform to dissolve the solid, and separated the organic layer. The aqueous phase was extracted with (20mL×3) chloroform, and the organic layer was washed three times with 2mol/L NaOH solution, then washed with water until pH=8-12, and dried over anhydrous NaSO ₄ . The solvent was evaporated to dryness, excess 1,2-dibromoethane was evaporated at 130°C, and the remaining solid was purified by recrystallization from petroleum ether, and the yield of intermediate I was 87%.

Second step: Add 6.08g (0.02mol) of 1-bromo-2(2,4,6-trichlorophenoxy)ethane (intermediate 1) With the solution of 35mL 95% ethanol, reflux reaction 17h. After natural cooling, the excess n-propylamine was evaporated under normal pressure, and the product was poured into 38mL of 20% hydrobromic acid solution under stirring, and a pale yellow solid was precipitated. After filtering, it was washed with carbon tetrachloride to obtain 6.2 g of white powdery solid, the yield 89%.

The third step: under ice-water bath cooling and stirring, drop 2.8g (0.0077 mol) N-2-[(2,4,6-trichlorophenoxy)ethyl]propylamine hydrobromide (intermediate II) mixed with 2.1mL (0.015mol) triethylamine, 10mL chloroform , and reacted for 0.5 hours after dropping, continued to drop a mixture of 0.5g (0.0077mol) imidazole, 2.1mL (0.015mol) triethylamine, and 10mL chloroform, and reflux for 5h. After the reaction was complete, the solvent was recovered, a large amount of water was added to wash the residual solid, and a mixed solvent of toluene and petroleum ether (volume ratio 1.1:1) was recrystallized to obtain 2.5 g of a white solid with a yield of 85%.

Example 2

Step 1: Take 75g (33.3mL, 0.4mol) of 1,2-dibromoethane in a 150mL three-neck flask, add 30mL of water, heat to boiling, add 2,4,6-trichloro Sodium phenoxide solution (dropped in about 1 hour), continued to reflux for 14 hours, stopped the reflux when the water phase was clear and pH = 7, cooled, added 12 mL of chloroform to dissolve the solid, and separated the organic layer. The aqueous phase was extracted with (20mL×3) chloroform, and the organic layer was washed three times with 2mol/L NaOH solution, then washed with water until pH=8-12, and dried over anhydrous NaSO ₄ . The solvent was evaporated to dryness, excess 1,2-dibromoethane was evaporated at 130°C, and the remaining solid was purified by recrystallization from petroleum ether, and the yield of intermediate I was 85%.

Second step: Add dropwise 3.04g (0.01mol) of 1-bromo-2(2,4,6-trichlorophenoxy)ethane (intermediate I ) and 20mL of 95% ethanol solution, reflux reaction 15h. After natural cooling, the excess n-propylamine was evaporated under normal pressure, and the product was poured into 20mL of 20% hydrobromic acid solution under stirring, and a pale yellow solid was precipitated. After filtering, it was washed with carbon tetrachloride to obtain 3.2 g of white powdery solid, the yield 92%.

The third step: under ice-water bath cooling and stirring, drop 5.6g (0.0154 mol) N-2-[(2,4,6-trichlorophenoxy)ethyl]propylamine hydrobromide (intermediate II) mixed with 4.0mL (0.029mol) triethylamine, 20mL chloroform , and reacted for 0.5 hours after dropping, continued to drop a mixture of 1.0 g (0.0154 mol) imidazole, 4.0 mL (0.029 mol) triethylamine, and 20 mL chloroform, and reflux for 6 h. After the reaction was complete, the solvent was recovered, a large amount of water was added to wash the residual solid, and a mixed solvent of toluene and petroleum ether (volume ratio 1:1) was recrystallized to obtain 4.8 g of a white solid with a yield of 82%.

Example 3

Step 1: Take 150g (66.7mL, 0.8mol) of 1,2-dibromoethane in a 250mL three-neck flask, add 50mL of water, heat to boiling, add 2,4,6-trichloro Sodium phenoxide solution (dropped in about 1 h), continued to reflux for 10 h, stopped the reflux when the water phase was clear and pH = 7, cooled, added 20 mL of chloroform to dissolve the solid, and separated the organic layer. The aqueous phase was extracted with (20mL×3) chloroform, and the organic layer was washed three times with 2mol/L NaOH solution, then washed with water until pH=8-12, and dried over anhydrous NaSO ₄ . The solvent was evaporated to dryness, excess 1,2-dibromoethane was evaporated at 130°C, and the remaining solid was recrystallized and purified with hexane, and the yield of intermediate I was 87%.

Step 2: Add 6.08g (0.02mol) of 1-bromo-2(2,4,6-trichlorophenoxy)ethane (intermediate 1) With the solution of 35mL 90% ethanol, reflux reaction 17h. After natural cooling, the excess n-propylamine was evaporated under normal pressure, and the product was poured into 38mL of 17% hydrobromic acid solution under stirring, and a light yellow solid was precipitated. After filtering, it was washed with petroleum ether to obtain 6.1 g of white powdery solid, with a yield of 88%. .

The third step: under ice-water bath cooling and stirring, drop 2.8g (0.0077 mol) N-2-[(2,4,6-trichlorophenoxy)ethyl]propylamine hydrobromide (intermediate II) mixed with 2.0mL (0.014mol) triethylamine, 10mL chloroform , and reacted for 0.5 hours after dropping, continued dropping a mixture of 0.5g (0.0077mol) imidazole, 2.0mL (0.014mol) triethylamine, and 10mL chloroform, and refluxed for 7h. After the reaction was complete, the solvent was recovered, a large amount of water was added to wash the residual solid, and a mixed solvent of toluene and petroleum ether (volume ratio 1.2:1) was recrystallized to obtain 2.5 g of a white solid with a yield of 85%.

Example 4

Step 1: Take 75g (33.3mL, 0.4mol) of 1,2-dibromoethane in a 150mL three-neck flask, add 30mL of water, heat to boiling, add 2,4,6-trichloro Sodium phenoxide solution (dropped in about 1.5 h), continued to reflux for 13 h, stopped the reflux when the water phase was clear and pH = 7, cooled, added 12 mL of chloroform to dissolve the solid, and separated the organic layer. The aqueous phase was extracted with (20mL×3) chloroform, and the organic layer was washed three times with 2mol/L NaOH solution, then washed with water until pH=8-12, and dried over anhydrous NaSO ₄ . The solvent was evaporated to dryness, excess 1,2-dibromoethane was evaporated at 130°C, and the remaining solid was purified by recrystallization with ether, and the yield of intermediate I was 84%.

Step 2: Add 3.04g (0.01mol) of 1-bromo-2(2,4,6-trichlorophenoxy)ethane (intermediate 1) With the solution of 20mL 85% ethanol, reflux reaction 15h. After natural cooling, the excess n-propylamine was evaporated under normal pressure, and the product was poured into 20mL of 30% hydrobromic acid solution under stirring, and a pale yellow solid was precipitated. After filtering, it was washed with carbon tetrachloride to obtain 3.2 g of white powdery solid, the yield 92%.

The third step: under ice-water bath cooling and stirring, drop 5.6g (0.0154 mol) N-2-[(2,4,6-trichlorophenoxy)ethyl]propylamine hydrobromide (intermediate II) mixed with 4.0mL (0.029mol) triethylamine, 20mL chloroform , and reacted for 0.5 hours after dropping, continued to drop a mixture of 1.0 g (0.0154 mol) imidazole, 4.0 mL (0.029 mol) triethylamine, and 20 mL chloroform, and reflux for 8 h. After the reaction was complete, the solvent was recovered, a large amount of water was added to wash the residual solid, and a mixed solvent of toluene and petroleum ether (volume ratio 0.8:1) was recrystallized to obtain 4.9 g of a white solid with a yield of 83%.

Claims (10)

1, a kind of preparation method of imidamide is characterized in that comprising the steps: (1) 1,2-dibromoethane reacts with 2,4,6-trichlorophenate sodium to synthesize 1-bromo-2-(2,4,6-trichlorophenoxy)ethane, which is called intermediate Body I: 1,2-dibromoethane and 2,4,6-trichlorophenol sodium solution were refluxed for 5-15 hours, and the reflux was stopped when the aqueous phase was clear and pH=7. (2) Intermediate I reacts with n-propylamine in ethanol solution to prepare N-2-[(2,4,6-trichlorophenoxy) ethyl] propylamine hydrobromide, which is called intermediate II; (3) In the presence of trichloromethyl carbonate and triethylamine, N-n-propyl-N-[2-(2,4,6-tri Chlorophenoxy) ethyl] carbamoyl imidazole, i.e. imidamide. 2. The method according to claim 1, characterized in that in step (1), after the reaction between 1,2-dibromoethane and 2,4,6-trichlorophenol sodium finishes, add chloroform to dissolve the solid, separate The oil layer is released, the solvent and excess 1,2-dibromoethane are recovered, the residual liquid is cooled to solidify, suction filtered, and organic solvent is recrystallized to obtain 1-bromo-2-(2,4,6-trichlorophenoxy) ethane. 3. The method according to claim 2, characterized in that the organic solvent used for recrystallization is petroleum ether, n-hexane or ether. 4. The method according to claim 1, characterized in that in step (2), the volume fraction of the ethanol solution is 75-100%, and the reflux time for the reaction between intermediate I and n-propylamine is 10-30 hours. 5. The method according to claim 4, characterized in that after the reaction is complete, the solvent and excess n-propylamine are reclaimed, the residue is treated with hydrobromic acid, solidified, suction filtered, and washed with an organic solvent to obtain N-2-[(2 , 4,6-trichlorophenoxy)ethyl]propylamine hydrobromide. 6. The method according to claim 5, characterized in that the concentration of hydrobromic acid used for residue treatment is 15%-48% by mass. 7. The method according to claim 5, characterized in that the organic solvent used for washing is petroleum ether, n-hexane, diethyl ether, or carbon tetrachloride. 8. The method according to claim 1, characterized in that in step (3), add the chloroform solution of intermediate II and triethylamine dropwise to the chloroform solution of trichloromethyl carbonate, then add imidazole and triethylamine The chloroform solution of ethylamine is refluxed for 4 to 8 hours, the molar ratio of triethylamine to intermediate II is 1.0 to 2.5:1, and the molar ratio of trichloromethyl carbonate to intermediate II is 0.38 to 0.33:1.00. 9. The method according to claim 8, characterized in that after the reaction is complete, the solvent is recovered, water is added to wash the residual solid, and a mixed solvent of toluene and petroleum ether is recrystallized to obtain N-n-propyl-N-[2-(2, 4,6-trichlorophenoxy)ethyl]carbamoyl imidazole, namely imidamide. 10. The method according to claim 9, characterized in that the volume ratio of toluene to petroleum ether is 1.2-0.8:1.